Apoptosis is a normal physiologic process that leads to individual cell death. This process of programmed cell death is involved in a variety of normal and pathogenic biological events and can be induced by a number of unrelated stimuli. Changes in the biological regulation of apoptosis also occur during aging and are responsible for many of the conditions and diseases related to aging. Recent studies of apoptosis have implied that a common metabolic pathway leading to cell death may be initiated by a wide variety of signals, including hormones, serum growth factor deprivation, chemotherapeutic agents, ionizing radiation and infection by human immunodeficiency virus (HIV). Wyllie (1980) Nature, 284: 555-556; Kanter et al. (1984) Biochem. Biophys. Res. Commun. 118: 392-399; Duke and Cohen (1986) Lymphokine Res. 5: 289-299; Tomei et al. (1988) Biochem. Biophys. Res. Commun. 155: 324-331; Kruman et al. (1991) J. Cell. Physiol. 148: 267-273; Ameisen and Capron (1991) Immunology Today 12: 102; and Sheppard and Ascher (1992) J. AIDS 5: 143. Agents that modulate the biological control of apoptosis thus have therapeutic utility in a wide variety of conditions.
Apoptotic cell death is characterized by cellular shrinkage, chromatin condensation, cytoplasmic blebbing, increased membrane permeability and interchromosomal DNA cleavage. Kerr et al. (1992) FASEB J. 6: 2450; and Cohen and Duke (1992) Ann. Rev. Immunol. 10: 267. The blebs, small, membrane-encapsulated spheres that pinch off of the surface of apoptotic cells, may continue to produce superoxide radicals which damage surrounding cell tissue and may be involved in inflammatory processes.
Bcl-2 was discovered at the common chromosomal translocation site t(14:18) in follicular lymphomas and results in aberrant over-expression of bcl-2. Tsujimoto et al. (1984) Science 226: 1097-1099; and Cleary et al. (1986) Cell 47: 19-28. The normal function of bcl-2 is the prevention of apoptosis; unregulated expression of bcl-2 in B cells is thought to lead to increased numbers of proliferating B cells which may be a critical factor in the development of lymphoma. McDonnell and Korsmeyer (1991) Nature 349: 254-256; and, for review see, Edgington (1993) Bio/Tech. 11: 787-792. Bcl-2 is also capable of blocking of .gamma. irradiation-induced cell death. Sentman et al. (1991) Cell 67: 879-888; and Strassen (1991) Cell 67: 889-899. It is now known that bcl-2 inhibits most types of apoptotic cell death and is thought to function by regulating an antioxidant pathway at sites of free radical generation. Hockenbery et al. (1993) Cell 75: 241-251.
While apoptosis is a normal cellular event, it can also be induced by pathological conditions and a variety of injuries. Apoptosis is involved in a wide variety of conditions including but not limited to, cardiovascular disease, cancer regression, immunoregulation, viral diseases, anemia, neurological disorders, gastrointestinal disorders, including but not limited to, diarrhea and dysentery, diabetes, hair loss, rejection of organ transplants, prostate hypertrophy, obesity, ocular disorders, stress and aging.
Bcl-2 belongs to a family of proteins some of which have been cloned and sequenced. Williams and Smith (1993) Cell 74: 777-779. It has been shown that various Bcl-2 members have the ability to associate with one another as heterodimers. Itavi et al. (1993) Cell 74: 609-619; and Sato et al. (1994) Proc. Natl. Acad. Sci. USA 91: 9238-9242. Additionally, BHRF1 displays a 25% sequence identity to Bcl-2 (Cleary et al. (1986) Cell 47: 19-28) and has been shown by gene transfer studies to protect B cells from programmed cell death. Henderson et al. (1993) Proc. Natl. Acad. Sci. USA 90: 8479-8483.
The herpesvirus family of viruses typically produce latent and recurrent infections. Herpesvirus genomes are composed of sequences with a short and a long region. Herpesvirus particles have a diameter from 180 nm to 200 nm. Many particles do not contain envelopes. Typically the DNA is wrapped around an associated protein. The herpesvirus has a tendency to persist in a quiescent state for irregular periods of time.
All references cited herein, both supra and infra, are hereby incorporated by reference herein.